Method for accurate and low-consumption MEMS micropump actuation and device for carrying out said method

ABSTRACT

The present invention describes the improvements due to alternated actuation cycles to reduce the delivery errors related to the pumping chamber elasticity, the actuator relaxation or hysteresis. The method actuates a pumping device with an optimal driving voltage profile, wherein the pumping device comprises a pumping chamber including a pumping membrane and a voltage controlled actuator connected to said membrane; the movement of said membrane being defined by three positions, namely a rest, a bottom and a top position. The method includes the actuation of the membrane with a pumping pattern including at least two different cycles: Cycle A: rest-bottom-rest-top-rest Cycle B: rest-top-rest-bottom-rest. The invention also relates to a device to carry out the method.

This application is a continuation of U.S. application Ser. No.14/235,090, filed Jan. 27, 2014, which is the U.S. national phase ofInternational Application No. PCT/IB2012/053847 filed Jul. 27, 2012which designated the U.S. and claims priority to EP Patent ApplicationNo. 11176003.9 filed Jul. 29, 2011, the entire contents of each of whichare hereby incorporated by reference.

FIELD OF INVENTION

The present invention is related to insulin pumps having a pumpingchamber, a pumping membrane and a voltage driven actuator and twovalves.

More specifically, the present invention relates to an improved methodfor accurate and low-consumption actuation profile of membranemicropump, typically for basal infusion of insulin.

PRIOR ART

Reciprocating displacement micropumps have been the subject of anextensive interest. A comprehensive review on the development ofmicroscale devices for pumping fluids has been published by D. J. Laserand J. G. Santiago, J. Micromech. Microeng. 14 (2004) R35-R64. Amongthese various kinds of devices, the present invention is morespecifically related to reciprocating displacement pump having two checkvalves and a fixed stroke.

The patent application EP 1403519 A1 discloses a membrane pump withstretchable polyimide pump membrane that is moved periodically, using anactuator, between two positions corresponding to a maximum and minimumvolume positions where the pump membrane is stretched alternativelyagainst a first and a second wall respectively.

MEMS micropumps are described, for example, in the patent publicationsUS 2006/027523 and WO 2010/046728 A1. This known MEMS micropump 1 asillustrated in FIG. 1 is a highly miniaturized and reciprocatingmembrane pumping mechanism. It is made from silicon or silicon andglass, using technologies referred to as MEMS (Micro-Electro-MechanicalSystem). It contains an inlet control member, here an inlet valve 2, apumping membrane 3, a functional inner detector 4 which allows detectionof various failures in the system and an outlet valve 5. The principleof such micro-pumps is known in the prior art, for example from U.S.Pat. No. 5,759,014, the content of which is incorporated by reference inthe present application.

FIG. 1 illustrates a micropump with the stack of a glass layer as baseplate 8, a silicon layer as second plate 9, secured to the base plate 8,and a second glass layer 10 as a top plate, secured to the silicon plate9, thereby defining a pumping chamber 11 having a volume.

An actuator (not represented here) linked to the mesa 6 allows thecontrolled displacement of the pumping membrane 3 between the plates 10and 8, and more specifically on the anti-bonding layers 21 and 22 (arrayof tiny square pads on FIGS. 1 and 2) of said plates 10 and 8. Thesesplates 10 and 8, having or not anti-bonding layers, are respectively abottom and a top mechanical stops for the pumping membrane 3. A channel7 is also present in order to connect the outlet control member, theoutlet valve 5 to the outer detector not represented here and finally tothe outlet port placed on the opposite side of the pump.

The FIG. 2 illustrates another cross-section of the MEMS micropumpincluding a cover 12 onto the channel 7, an outer detector 13 and afluidic channel 17 between the outer detector 13 and the outlet port 18.

In the pump 1, the pressure inside the pumping chamber varies during apumping cycle depending on numerous factors, such as the actuation rate,the pressure at the inlet and the outlet, the potential presence of abubble volume, the valve characteristics and their leak rates.

Dysfunctions are detected by analysing the pressure profile duringactuation cycles.

The inner pressure sensor 4 and outer pressure sensor 13 in themicro-pump 1 are made of a silicon membrane placed between the pumpingchamber 11 and the pump outlet 5 and between the pump outlet valve 5 andpump outlet port 18 respectively. The sensors are located in a channelformed between the surface of the micro-pumps silicon layer 9 and itstop layer 10. In addition, the sensors comprise a set of strainsensitive resistors in a Wheatstone bridge configuration on themembrane, making use of the huge piezo-resistive effect of the silicon.A change of pressure induces a distortion of the membrane and thereforethe bridge is no longer in equilibrium. The sensors are designed to makethe signal linear with the pressure within the typical pressure range ofthe pump. The fluid is in contact with the surface of theinterconnection leads and the piezo-resistors. A good electricalinsulation of the bridge is ensured by using an additional surfacedoping of polarity opposite to that of the leads and thepiezo-resistors.

During the filling, the mesa pulls the membrane against the bottommechanical stop; the outlet remains close while the inlet opens when theunderpressure in the pumping chamber reaches the inlet valve pretension.During the infusion, the actuator pushes the mesa and therefore thepumping membrane against the upper mechanical stop, inducing anoverpressure that opens the outlet valve and maintains the inlet closed.

The device is called a “push-pull” device because the membrane should bepushed to reach the upper stop and pulled to reach the lower stop, itsrest position being located more or less at the middle of the stroke,i.e. at the same distance of the two mechanical stops.

The document WO 2010/046728 discloses methods for periodical actuationsof a membrane pump, each cycle comprising at least one suction phase andone discharge phase being eventually followed by stationary phases, thepumping chamber volume returning to its initial size at the end of thecycle. The standard single pumping actuation profile as described in WO2010/046728 is shown FIG. 3. Because maintaining a high voltage onto thepiezo actuator electrode is not optimal in terms of power consumption,the stroke is decomposed into a first positive half stroke (hereaftercalled ½ push), a full negative stroke (full pull or full filling) andfinally a second positive half push to complete to actuation cycle.Positive displacement corresponds to an infusion from the pumpingchamber toward the patient while negative displacement corresponds tothe filling of the pumping chamber from the reservoir.

The nominal single pumping voltage profile is built to ensure that thepumping membrane always reaches the mechanical stops in normal andforeseeable conditions of use.

The pumping chamber has two valves having pretensions, respectivelyP_(val in) for the inlet valve and P_(val out) for the outlet valve.During the normal functioning of the pump, the pressure at the end ofthe pumping cavity filling is negative and equal to P_(val in) while atthe end of the infusion this pressure becomes positive and equal toP_(val out).

In bolus mode, there is a tiny effect of the pumping chamber elasticityon the delivery accuracy because the pumping membrane is movingcontinuously between the two stop limiters and the pumping membrane isnever free to move while the valves are closed.

The pumping membrane is therefore either in movement or against a stoplimiter. The maximum volume change in that configuration, when thepressure varies from the valve opening pressure towards zero, is ideallylimited to less than 1 nl (detector and outlet valve and membrane volumevariation). The elasticity of the system is only increased at the end ofthe last half stroke of the bolus infusion, when the released membraneis “free”.

In basal mode the effect of the pumping chamber elasticity on thedelivery accuracy depends on the actuation cycle.

Let us consider the standard actuation cycle made of:

-   -   1. an half “push”, the membrane moving from its rest position        (located between the top and the bottom mechanical stops)        towards the top    -   2. a full “pull”, the membrane moving from the top towards the        bottom mechanical stops    -   3. a second half “push”, the membrane moving from the bottom        towards its rest position

During the steps 1 and 2, the effect of the pumping chamber elasticityis limited but during the last half push, because the piezo is no longerpowered, the overall elasticity of the pumping chamber is significantlyincreased by the contribution to the “free” membrane.

The volume change per 100 mbar in the configuration 3 could be up to oneor two orders of magnitude larger than in configuration 1 or 2. At theend of a basal stroke, just after the closing of the outlet valve, themembrane could be shifted of several microns from it rest position andthe nominal stroke volume is therefore not completely infused. Thepressure will therefore release from the pressure P_(val out) towardszero in normal conditions of pressure (inlet pressure=outletpressure=0). During the pressure decay, a residual volume will beinfused towards both inlet and outlet via the residual fluidicresistances of the normally “closed” valves.

If the fluidic resistance of the inlet is much larger than the fluidicresistance of the outlet, the effect on the accuracy is negligible: theresidual volume will be infused through the outlet and the nominalstroke volume is obtained.

But in the worst case, considering the residual fluidic resistance ofthe closed inlet is much smaller than the outlet, the residual volumewill be infused towards the inlet (backflow), leading to anunderinfusion that can be as large as 10% or more of the nominal strokevolume.

Because the ratio between the residual fluidic resistances of the closedvalves is purely random, the underinfusion due to the effect discussedabove is also purely random.

According to the methods described in the document WO 2010/046728,typical actuation cycles are made of repetition of suction and dischargephases with eventually stationary phases during which the pumping volumedoes not change, indicating that the pumping membrane is against a stoplimiter according during said stationary phases. There is therefore nopossibility to have a stationary phase, within a given actuation cycle,when the pumping membrane is for instance in between the two stoplimiters.

According to the methods presented in WO 2010/046728 the pumpingmembrane is forced to perform pumping cycles wherein the pumpingmembrane moves alternatively between the two stop limiters. But sincethe actuation cycle is assumed as repetitive, the principle ofalternative movement between the two stop limiters is kept during thetransition between the end of the cycle and the beginning of thefollowing cycle which will continue the move of the membrane up to thesecond stop limiter.

All of these methods are conform to the intuitive way to perform pumpingcycle with accuracy using a membrane pump having stop limiters: startingfrom an initial position, reaching alternatively each stop limiter andreturning to its original position at the end of the cycle.

There is therefore a need to provide a new actuation profile that makesthis random error a systematic error that is not device dependent andthat can therefore being compensated.

GENERAL DESCRIPTION OF THE INVENTION

The present invention offers several improvements with respect tostate-of-the-art methods.

It refers to a method and a device as defined in the claims.

The object according to the present invention also comprises a MEMSmicropump as defined e.g. in US patent application US 2006/027523 andPCT application WO 2010/046728. The contents of those documents areincorporated by reference in the present application

Considering reciprocating pumps as described in the state-of-the-art,there is a way to transform the erratic error due to pumping chamberelasticity into a systematic error that can be compensated.

A solution proposed in the present invention is to use a specificpumping pattern that comprise a ½ push (respectively ½ pull) followed bya ½ pull (respectively ½ push). This pumping pattern is not natural fora usual pump and it permits to improve the accuracy of the pump.

In a preferred embodiment, the pumping device comprises a pumpingchamber including a pumping membrane and an actuator connected to saidmembrane. The movement of said membrane is defined by three positions,namely a rest position, a bottom position and a top position; whereinthe rest position is comprised between the bottom and the top positions,and wherein said top, rest and bottom positions correspond to a minimum,intermediate and maximum volume of the pumping chamber respectively.

In the preferred embodiment, said pumping pattern comprises alternatingat least a ½ push/full pull/½ push cycle with a ½ pull/full push/½ pullcycle, the pumping membrane reaching two times consecutively the samestop limiter during this phase consisting in a partial suction phasefollowed by a partial discharge phase or vice versa.

By this mean, the pressure at the end of the basal stroke isalternatively positive and negative, inducing a balance of the back-flowevery two cycles: the underdelivery becomes systematic and can becompensated.

In another embodiment, the pumping device further comprises an inletchannel which is connected to a reservoir, an outlet channel which isconnected to a patient line, a valve located at the inlet channel whichhas a fluidic resistance named Rin and a valve located at the outletchannel which has a fluidic resistance named Rout. The pumping pattern aratio St_(push)/St_(pull) which depends of the ratio R_(in)/R_(out),where St_(push) is the number of stop to the rest position preceded by apartial push and St_(pull) is the number of stop to the rest positionpreceded by a partial pull. Furthermore, if the ratio R_(in)/R_(out) isequal to 1 or unknown, then the ratio St_(push)/St_(pull) must be equalto 1; if the ratio R_(in)/R_(out) is less than 1, then the ratioSt_(push)/St_(pull) must be less than 1; if the ratio R_(in)/R_(out) isgreater than 1, then the ratio St_(push)/St_(pull) must be greaterthan 1. This pumping pattern may change over time if the ratioR_(in)/R_(out) changes.

This method, still based on the low consumption concept of WO2010/046728(the piezo is not powered between each stroke), avoids the random erroron the delivery accuracy at basal rate due to the elasticity of thereleased pumping membrane.

Specific pumping pattern to prevent delivery errors due to actuatorrelaxation or hysteresis are also proposed in the present invention.

Finally a bolus algorithm is described in order to minimize the deliveryerror due to the difference between bolus nominal stroke volume and theminimum programmable increment for the bolus volume.

LIST OF FIGURES

FIG. 1 is a cross-section of the MEMS micropump;

FIG. 1A shows a cross-hatched version of FIG. 1;

FIG. 2A shows a cross-hatched version of FIG. 2;

FIG. 2 shows the cross-section of the MEMS micropump including bothdetectors and showing the fluidic pathway;

FIG. 3 shows a standard single shot actuation profile according to WO2010/046728 for both basal and bolus modes;

FIG. 4 is a graph of relative infusion error due to the bolus algorithm;

FIG. 5 shows different pumping pattern;

FIGS. 6 and 6′ show a pumping pattern which has as much half pullfollowed by a stop to the rest position as half push followed by a stopto the rest position;

FIGS. 7 and 7′ show a pumping pattern which has less half pull followedby a stop to the rest position than half push followed by a stop to therest position;

FIGS. 8 and 8′ show a pumping pattern which has more half pull followedby a stop to the rest position than half push followed by a stop to therest position;

FIG. 9 shows a pumping pattern which change overtime;

FIG. 10 shows a reservoir connected to a pump, having an inlet valve andan outlet valve, connected to a patient line;

FIG. 11 illustrates a table that shows the direction of the flows (largeblack arrows) during a cycle B; and

FIG. 12 illustrates a table that shows the direction of the flows (largeblack arrows) during a cycle A.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Stroke

The stroke corresponds here to a full cycle of the pumping membrane,starting from an initial position, reaching iteratively the twomechanical stops and finally coming back to its initial position.

Stroke Volume

Volume change of the pumping cavity, at equilibrium, when the pumpingmembrane is displaced from the first mechanical stop towards the secondmechanical stop.

This stroke volume is the nominal stroke volume or geometrical strokevolume. The stroke volume is equal to the volume injected during astroke for a pump having valves with opening threshold equal to zero.

The stroke volume is here the minimum volume that can be infused withaccuracy.

The volume or the flow rate programmed by the user is decomposed in asequence of nominal stroke having the required intervals.

Basal and Bolus Stroke Volumes

Effective volume infused during a stroke in basal and bolus moderespectively.

Because the valves have pretensions, the elasticity of the pump has aneffect on the effective stroke volume or the volume infused during onestroke. This effect is different in basal and bolus mode.

Single Pumping Voltage Profile

Voltage profile applied to the actuator to perform a single stroke.

The nominal single pumping voltage profile is the basis profile for bothstandard basal and bolus mode.

This nominal single pumping voltage profile is suitable to get the rightstroke volume per cycle in normal conditions of temperature andpressure.

Pumping Pattern

Sequence of pumping deliveries.

The pumping unit delivers a pulsed flow rate made of sequence of singlepumping like syringe pumps.

The intervals between each stroke are adjusted to meet the programmedflow rate and could be regular or irregular.

Back-Flow

Leakage of at least one valve of the pump unit inducing an underdeliveryduring each stroke even in absence of gradient of pressure between theinlet and the outlet.

A back flow is typically due to the presence of large particles onto onevalve seat and affects both bolus and basal accuracies.

Stationary Phase

A stationary phase is a phase during which the actuator doesn't movesubstantially. One or more stationary phase may perform between thebeginning and the end of the pumping pattern.

For this invention, the stationary phase is characterized by the factthe fluid flows through at least one of said valves even if the bothcheck valves are in closed position.

The stationary phase permits a relaxation of the pressure in the pumpingchamber up to an equilibrium pressure. Said relaxation is due to achange of the volume of the fluid present in the pumping chamber inducedby a flow through both valves. Where said flow is driven by thedifference of pressure between the pumping chamber and both inlet andoutlet valves and by the residual fluidic resistances of said valveswhich are in closed positions. A stop to a position may be a stationaryphase.

Rest Position

The rest position is a position of the membrane in the pumping chamber.It is located between the top and the bottom position. Preferably, therest position is predetermined, non-random and different of top andbottom position.

The rest position and the stationary phase are different. When thepumping pattern performs a full push or a full pull, the membrane movesand goes through said rest position. A stop or a stationary phase atsaid rest position is possible but not mandatory.

For the present invention, the pumping device comprises a pumpingchamber including a pumping membrane and an actuator connected to saidmembrane, means for actuating the membrane according to a determinedpumping pattern, valves which may be a check valves and have apretension.

In the preferred embodiment, the volume change of the pumping chamber iscomprised between 0.5 nl to 50 nl per bar of applied pressure when thepumping membrane is against a mechanical stop, and between 10 nl to 500nl per bar of applied pressure when the pumping membrane is not againsta mechanical stop and when the actuator is not powered.

In one embodiment, the pumping device further comprises a pressuresensor within the pumping chamber and/or means for measuring the fluidicresistance at the inlet and at the outlet or the fluidic resistancedifference between the inlet and the outlet.

1.1. Method of Alternated Cycles

In basal mode the effect of the pumping chamber elasticity on thedelivery accuracy depends on the pumping pattern.

We consider that the valves (which may be a check valves) have the sameopening thresholds in absolute value:−P _(val in) =P _(val out) =P _(val)Let us consider a first pumping profile (standard single pumping profileor cycle B because the pressure is positive at the end of the actuation)made of:

-   -   1. a half “push”, the membrane moving from its rest position        (located between the top and the bottom mechanical stops)        towards the top    -   2. a full “pull”, the membrane moving from the top towards the        bottom    -   3. a second half “push”, the membrane being released from the        bottom towards its rest position

As discussed before, during the steps 1 and 2, the effect of the pumpingchamber elasticity is equivalent to the bolus mode with a perfectbalancing between the filling (pull) and the infusion (push). But duringthe last half push, because the piezo is no longer powered, the overallelasticity of the pumping chamber is significantly increased by thecontribution to the “free” membrane.

Let us consider now a second pumping profile (cycle A) made of:

-   -   4. a half “pull”, the membrane moving from its rest position        (located between the top and the bottom mechanical stops)        towards the bottom    -   5. a full “push”, the membrane moving from the bottom towards        the upper mechanical stops    -   6. a second half “pull”, the membrane being release from the        bottom towards its rest position

We consider R_(in) and R_(out) the fluidic resistances of the inlet andthe outlet valves submitted to a gradient of pressure lower than theiropening thresholds. We assume these resistances as constant in thatrange of pressure.

We note V_(r) the residual volume that will be infused at the end of thebasal stroke from the pumping chamber towards both inlet and outletvalves.

If the basal stroke ends by a “push”, i.e. a cycle B with a positivepressure in the pumping chamber, the underinfusion is due to an inletback-flow equal to:

$V_{r\; 1} = {\frac{R_{out}}{R_{in} + R_{out}}V_{r}}$

This formula shows explicitly that the underinfusion depends on theratio R_(in)/R_(out).

If the basal stroke ends by a “pull”, i.e. a cycle A with a negativepressure in the pumping chamber, the inderinfusion is due to an outletback-flow equal to:

$V_{r\; 2} = {\frac{R_{in}}{R_{in} + R_{out}}V_{r}}$

Considering two alternated pumping profiles, i.e. cycle B followed bycycle A or cycle A followed by cycle B, the overall underinfusion is nowequal to V_(r), leading to a mean underinfusion of V_(r)/2 per stroke.

The underinfusion is now systematic and does not depend on the ratioR_(in)/R_(out).

This error can be simply compensated during the calculation of theintervals between the basal strokes.

The cycles A and B presented here are non-limiting examples of themethod. Any other cycles including several intermediate positions can beused.

In one embodiment, the pumping pattern includes a number of cycles Awhich is equal or close to the number of cycles B over a given timeinterval.

The signal of the pressure sensor in the pumping chamber could beanalysed during actuation in order to determine all characteristicsnecessary to compute the pumping pattern, including the inlet and outletpressures, the valve pretensions, the stroke completion, the leakage,the presence of air . . . .

In another embodiment showed at the FIG. 6, the pumping pattern includesa stop to the rest position to each half push and half pull.

The FIGS. 6 and 6′ show the pumping pattern when the ratioR_(in)/R_(out) is unknown or equal to 1.

So, if the ratio R_(in)/R_(out) is unknown or equal to 1, the pumpingpattern must include as much Cycle A as Cycle B or in another word, thepumping pattern must include as much half pull followed by a stop to therest position as half push followed by a stop to the rest position. It'sthe same pumping pattern, if a valve leaks but we don't know which one.So if R_(in)/R_(out)=1, then St_(push)/St_(pull)=1.

The FIGS. 7 and 7′ show the pumping pattern when the ratioR_(in)/R_(out) is greater than 1.

So, if the ratio R_(in)/R_(out) is greater than 1, the pumping patternmust include less Cycle A than Cycle B or in another word, the pumpingpattern must include less half pull followed by a stop to the restposition than half push followed by a stop to the rest position. It'sthe same pumping pattern, if the outlet valve leaks. So ifR_(in)/R_(out)>1, then St_(push)/St_(pull)>1.

The FIGS. 8 and 8′ show the pumping pattern when the ratioR_(in)/R_(out) is less than 1.

So, if the ratio R_(in)/R_(out) is less than 1, the pumping pattern mustinclude more Cycle A than Cycle B or in another word, the pumpingpattern must include more half pull followed by a stop to the restposition than half push followed by a stop to the rest position. It'sthe same pumping pattern, if the inlet valve leaks. So ifR_(in)/R_(out)<1, then St_(push)/St_(pull)<1.

In one embodiment, the pumping device comprises a reservoir. In thiscase, the pumping pattern may depend of the reservoir level because thefluidic resistance may depend of the reservoir level. So, the FIG. 9shows three time T1, T2 and T3. When the reservoir is full,R_(in)/R_(out) may be less than 1. Thus, during this time T1, thepumping pattern should include a ratio St_(push)/St_(pull)<1 or moreCycle A than Cycle B. But when the reservoir is nearly empty,R_(in)/R_(out) may be greater than 1. Thus, during this time T3, thepumping pattern should include a ratio St_(push)/St_(pull)>1 or moreCycle B than Cycle A.

1.2. Detailed Method for Basal Infusion

We provide here a complete calculation of the basal stroke volumeincluding all terms.

Notations:

P_(val)=valve pretension or valve opening threshold in absolute value

V₀=dead volume of the pumping chamber

dV=volume change of the pumping chamber, when the membrane is against amechanical stop, after application of a pressure P_(val)

dV_(r)=volume change of the pumping chamber, when the membrane isreleased (no power on the piezo), after application of a pressureP_(val)

dV_(i)=part of the volume dV expulsed through the inlet (i=1) andthrough the outlet (i=2)

dV_(n)=part of the volume dV_(r) expulsed through the inlet (i=1) andthrough the outlet (i=2)

The maxima of dV_(i) and dV_(n) take the form (after a completerelaxation of the pumping chamber pressure):

$\quad\left\{ \begin{matrix}{{dV}_{1} = {\frac{R_{out}}{R_{in} + R_{out}}{dV}}} \\{{dV}_{2} = {\frac{R_{in}}{R_{in} + R_{out}}{dV}}} \\{{dV}_{r\; 1} = {\frac{R_{out}}{R_{in} + R_{out}}{dV}_{r}}} \\{{dV}_{r\; 2} = {\frac{R_{in}}{R_{in} + R_{out}}{dV}_{r}}}\end{matrix} \right.$

We assume that the rest position of the membrane is equidistant fromeach mechanical stop.

We analyse the volume change for the inlet, the pumping chamber and theoutlet at each step of the pumping profile B and pumping profile A fortwo extreme cases that can occur:

-   -   No pressure relaxation except during the release of the membrane        (pump very tight)    -   Full relaxation of the pressure after each move of the membrane        (pump safe but at the limit of the specifications in term of        tightness)

The volume infused during each step of the basal stroke is estimated aswell as the average of two alternate strokes as discussed before.

The tables 1 and 2 summarize the results:

TABLE 1 Volume changes during basal strokes for very tight pumps. Pumpstatus Pchamber V inlet Vchamber V outlet rest position 0 0 V₀ + S_(v)/20 ½ push +P_(val) 0 V₀ + dV S_(v)/2 − dV Full pull −P_(val) −S_(v) + 2dVV₀ + S_(v) − dV S_(v)/2 − dV ½ push (release) +P_(val) −S_(v) + 2dV V₀ +S_(v)/2 + dV_(r) + dV S_(v) − 3dV − dV_(r) ½ push (relax) relax to 0−(S_(v) − 2dV − dV₁ − dV_(r1)) V₀ + S_(v)/2 S_(v) − 2dV − dV₁ − dV_(r1)end of cycle B rest position 0 0 V₀ + S_(v)/2 0 ½ pull −P_(val)−S_(v)/2 + dV V₀ + S_(v) − dV 0 Full push +P_(val) −S_(v)/2 + dV V₀ + dVS_(v) − 2dV ½ pull −P_(val) −S_(v) + 3dV + dV_(r) V₀ + S_(v)/2 − dV_(r)− dV S_(v) − 2dV ½ pull (release) relax to 0 −(S_(v) − 2dV − dV₂ −dV_(r2)) V₀ + S_(v)/2 S_(v) − 2dV − dV₂ − dV_(r2) end of cycle A averageB and A −(S_(v) − 5dV/2 − dV_(r)/2) S_(v) − 5dV/2 − dV_(r)/2

TABLE 2 Volume changes during basal strokes for pumps at the limit ofthe specifications in term of leakage. Pump status Pchamber V inletVchamber V outlet rest position 0 0 V₀ + S_(v)/2 0 ½ push +P_(val) 0V₀ + dV S_(v)/2 − dV ½ push (relax) relax to 0 +dV₁ V₀ S_(v)/2 − dV +dV₂ Full pull −P_(val) −(S_(v) − dV) + dV₁ V₀ + S_(v) − dV S_(v)/2 −dV + dV₂ Full pull (relax) relax to 0 −S_(v) + dV V₀ + S_(v) S_(v)/2 −dV ½ push (release) +P_(val) −S_(v) + dV V₀ + S_(v)/2 + dV_(r) + dVS_(v) − 2dV − dV_(r) ½ push (relax) relax to 0 −(S_(v) − dV − dV₁ −dV_(r1)) V₀ + S_(v)/2 S_(v) − dV − dV₁ − dV_(r1) end of cycle B restposition 0 0 V₀ + S_(v)/2 0 ½ pull −P_(val) −S_(v)/2 + dV V₀ + S_(v) −dV 0 ½ pull (relax) relax to 0 −S_(v)/2 + dV₂ V₀ + S_(v) −dV₂ Full push+P_(val) −S_(v)/2 + dV₂ V₀ + dV S_(v) − dV − dV₂ Full push (relax) relaxto 0 −S_(v)/2 + dV V₀ S_(v) − dV ½ pull (release) −P_(val) −S_(v) +2dV + dV_(r) V₀ + S_(v)/2 − dV_(r) − dV S_(v) − dV ½ pull (relax) relaxto 0 −(S_(v) − dV − dV₂ − dV_(r2)) V₀ + S_(v)/2 S_(v) − dV − dV₂ −dV_(r2) end of cycle A average B and A −(S_(v) − 3dV/2 − dV_(r)/2) S_(v)− 3dV/2 − dV_(r)/2

A sketch of the pump under actuation is provided in the table that isshown in FIG. 10 for the cycle B wherein a total pressure relaxationtakes place after each actuation step. To illustrate the effect ofelasticity we represent here the detector membrane that is deflecteddownwardly (resp. upwardly) for positive (resp. negative) pressure inthe pumping chamber. The directions of the flows are represented at eachstep of the cycle by large black arrows.

In the table that is shown in FIG. 11, the same illustrative sketch isprovided for the cycle A.

According to the method described here above, the average stroke volumefor two alternated cycles B and A only depend on dV and dV_(r) but noton the ratio R_(in) over R_(out).

Basal Stroke Volume with Alternate Cycles

The basal stroke volume finally takes the form, using alternated pumpingprofiles:

${S_{v}\left( {{alternate}\mspace{14mu}{basal}} \right)} = {S_{v} - \frac{{dV}_{r}}{2} - {{2\;{dV}} \pm \frac{dV}{2}}}$

EXAMPLE

dV=0.48 nl

dV_(r)=8.28 nl

We obtain an error of +/−0.24 nl.

We consider now the residual error due to the tolerance on the valvepretensions.

This residual error is based on a tolerance of 20% at 3 sigma (target10%).

Because dV and dV_(r) vary linearly with the valve pretensions, weobtain finally:error(alternate basal stroke)=±1.26 nlThe residual error of +/−1.26 nl due to the elasticity cannot becompensated except by measuring the valve pretension with accuracyduring the pump functioning.

It is important to note that the compensation of the elasticity effecton accuracy by using alternate strokes is not valid at high flow rate(more than 10 U/h or 0.1 ml/h for U100 insulin) because the pressure maynot relax completely between each stroke.

Basal Stroke Volume without Alternate Cycles (Standard Cycle)

${S_{v}\left( {{standard}\mspace{14mu}{basal}} \right)} = {{S_{v} - {dV} - {dV}_{1} - {dV}_{r\; 1}} = {S_{v} - {dV} - {\frac{{dV} + {dV}_{r}}{2} \pm \frac{{dV} + {dV}_{r}}{2}}}}$

We obtain an error of +/−4.38 nl.

The residual error on the valve pretension leads to the final value ofthe standard basal stroke volume:error(standard basal stroke)=±5.35 nlThe error due to the elasticity of the pump is here +/−5.35 nl.1.3. Detailed Method to Compensate Piezo Hysteresis

Piezo actuators driven in open loop show hysteresis and relaxation.Because the actuator is overdriven against the mechanical stops, thesingle effect of hysteresis and relaxation is met during the release ofthe actuator and more especially using alternated pumping profiles B andA.

When the pumping profile ends by a ½ pull (resp. a ½ push), the restposition of the membrane is slightly shifted from the initial neutralposition due to piezo hysteresis and relaxation. This shift stronglydepends on the interval duration between strokes. To simplify, thedifference between the rest positions of the membrane after pumpingprofiles B and A is called hereafter hysteresis.

Once the electrodes are short-circuited, PZT piezo bimorphs showtypically a total hysteresis of 0.8 um after 30 seconds, 0.5 um after 60seconds and only 0.1 um after 5 minutes.

Below 0.5 U/h the effect is negligible.

At higher basal rate, there is two ways to compensate the effect ofhysteresis and relaxation of the piezo for alternated pumping profiles:

-   -   1. compensation=change of the basal stroke volume    -   2. specific pumping cycle=reduction of the number of consecutive        alternate cycles        Compensation Method

The volume infused during each step of the basal stroke is estimated aswell as the average of two alternated pumping profiles as discussedbefore.

We note h the ratio between the total hysteresis and the stroke in %.

The tables 5 and 6 summarize the results.

TABLE 5 Volume changes during basal strokes for very tight pumps. Pumpstatus Pchamber V inlet Vchamber V outlet rest position A 0 0 V0 + SV(1− h)/2 0 ½ push +P_(val) 0 V0 + dV SV(1 − h)/2 − dV Full pull −P_(val)−SV + 2dV V0 + SV − dV SV(1 − h)/2 − dV ½ push +P_(val) −SV + 2dV V0 +SV(1 + h)/2 + dVr + dV SV(1 − h) − 3dV − dVr (release) ½ push (relax)relax to 0 −(SV − 2dV − dV1 − dVr1) V0 + SV(1 + h)/2 SV(1 − h) − 2dV −dV1 − dVr1 end of cycle B rest position B 0 0 V0 + SV(1 + h)/2 0 ½ pull−P_(val) −SV(1 − h)/2 + dV V0 + SV − dV 0 Full push +P_(val) −SV(1 −h)/2 + dV V0 + dV SV − 2dV ½ pull −P_(val) −SV(1 − h) + 3dV + dVr V0 +SV(1 − h)/2 − dVr − dV SV − 2dV ½ pull relax to 0 −(SV(1 − h) − 2dV −dV2 − dVr2) V0 + SV/2 SV − 2dV − dV2 − dVr2 (release) end of cycle Aaverage B and A −(SV(1 − h/2) − 5dV/2 − dVr/2) SV(1 − h/2) − 5dV/2 −dVr/2

TABLE 6 Volume changes during basal strokes for pumps at the limit ofthe specifications in term of leakage. Pump status Pchamber V inletVchamber V outlet rest position A 0 0 V0 + SV(1 − h)/2 0 ½ push +P_(val)0 V0 + dV SV(1 − h)/2 − dV ½ push (relax) relax to 0 +dV1 V0 SV(1 − h)/2− dV + dV2 Full pull −P_(val) −(SV − dV) + dV1 V0 + SV − dV SV(1 − h)/2− dV + dV2 Full pull (relax) relax to 0 −SV + dV V0 + SV SV(1 − h)/2 −dV ½ push (release) +P_(val) −SV + dV V0 + SV(1 + h)/2 + dVr + dV SV(1 −h) − 2dV − dVr ½ push (relax) relax to 0 −(SV − dV − dV1 − dVr1) V0 +SV(1 + h)/2 SV(1 − h) − dV − dV1 − dVr1 end of cycle B rest position B 00 V0 + SV(1 + h)/2 0 ½ pull −P_(val) −SV(1 − h)/2 + dV V0 + SV − dV 0 ½pull (relax) relax to 0 −SV(1 − h)/2 + dV2 V0 + SV −dV2 Full push+P_(val) −SV(1 − h)/2 + dV2 V0 + dV SV − dV − dV2 Full push (relax)relax to 0 −SV(1 − h)/2 + dV V0 SV − dV ½ pull (release) −P_(val) −SV(1− h) + 2dV + dVr V0 + SV(1 − h)/2 − dVr − dV SV − dV ½ pull (relax)relax to 0 −(SV(1 − h) − dV − dV2 − dVr2) V0 + SV(1 − h)/2 SV − dV − dV2− dVr2 end of cycle A average B and A −(SV(1 − h/2) − 3dV/2 − dVr/2)SV(1 − h/2) − 3dV/2 − dVr/2

At 1.2 U/h, for a cycle B followed by a cycle A or a cycle A followed bya cycle B, the mean stroke volume reduction for the two consecutivestrokes is equal to 1% or 2 nl. Because this error is systematic thenominal stroke volume can be adjusted to compensate the hysteresiseffect.

We suppose a max variation of 20% on the effect of hysteresis fordifferent batches of piezo.

The final error on the stroke volume using alternate cycle withcompensation of both elasticity and hysteresis become, at 1.2 U/h:error(alternate basal stroke)=±1.66 nlThe effective stroke volume is reduced of 2 nl.

The compensation should be calculated for each basal rate larger than0.5 U/h.

The flow rate and error estimation given here are non-limiting examplesof the method.

Specific Pumping Cycle Method

Hysteresis or relaxation changes the stroke volume only for twoconsecutive alternate actuations at moderate or high basal rate.

To reduce the effect of hysteresis/relaxation, the method comprises notalternating each time a cycle B with a cycle A but to perform Y cycles Bfollowed by Y cycles A. The mean effect due to the hysteresis is dividedby a factor Y.

At 2.4 U/h, using a pumping cycle made of 5 cycles B followed by 5cycles A, the effect of the hysteresis is equal to a mean reduction ofthe stroke volume equal to (0.5*0.8*200.64)/24.75/5=0.64 nl.

The accuracy error due to elasticity and piezo hysteresis becomes:error(alternate basal stroke)=±1.39 nlIncreasing the number Y of cycles reduces the relative error due tohysteresis and relaxation.

This actuation profile is suitable to compensate the effect ofelasticity and to make the effect of hysteresis negligible.

The method is not limited to the use of a piezo actuator but includesSMA, electromagnetic, capacitive, magnetic, magnetostrictive or anyother actuators.

1.4. Other Methods

Any other cycles C, D . . . including several intermediate positions canbe used for all of these methods. The numbers N_(i) of cycles i, wherei=A, B, C . . . , may be different between each others.

As non-limiting example, the cycle C could be a simple time intervalwithout any actuation.

A cycle may be a simple half positive and negative stroke from the restposition of the membrane towards a top and a bottom positionsrespectively.

Considering the cycles A and B, non-limiting examples are given below:

-   -   ABABAB . . .    -   AABBAABB . . .    -   A . . . AB . . . BA . . . AB . . . B . . .    -   ABAABABABBAB . . .    -   AB . . . BAB . . . BAB . . . BA . . .    -   A . . . ABA . . . ABA . . . AB . . .    -   . . .

Considering the additional cycle C, we can actuate the pumping membraneaccording to:

-   -   ABCABCABC . . .    -   AB . . . BCA . . . ABA . . . ABC . . .    -   A . . . AB . . . BC . . . CA . . . AB . . . BC . . . C . . .    -   ABCBABCBA . . .    -   ABCBACABCBAC . . .    -   ABACBABACBA . . .    -   AB . . . BC . . . CAB . . . BC . . . C . . .    -   ABC . . . C ABC . . . CABC . . . C . . .    -   A . . . AB . . . BCA . . . AB . . . BC . . .    -   A . . . ABC . . . CA . . . ABC . . . C . . .    -   AB . . . BC . . . CAB . . . BC . . . CAB . . . BC . . . C    -   . . .

The time periodicity is not mandatory: any of the preceding examples ofpumping pattern can have a time interval between strokes that is notconstant. The perfect periodicity in term of type of cycles is no longermandatory: e.g. the algorithm that defines the pumping pattern can useany input or trigger, e.g. the pumping pattern should for instancesimply ensure that the overall number N_(i) of cycles i is more or lesswithin the target for a predefined time interval. In practice a countercan be used to that end.

The pumping device includes any processing means including hardware(processors), embedded software . . . to compute and determine thepumping pattern according to the methods described in the presentinvention.

Pumping pattern may comprise preferably (or only) cycles A or cycles Bif the probability to get permanent opening or particles on one specificvalve by contrast to the other one is large: according to the flowdirection, the inlet valve may have a higher probability to be submittedfirst to particles coming from the reservoir. In the latter case, as analternative to the method described previously, the pumping patterncould comprise only cycles of type A which end by a half filling of thepumping chamber, the relative pressure in the pumping chamber beingtherefore negative after the cycle completion. Once the inlet valvecloses, the residual flow that takes place to equilibrate the pressureswill mainly occur between the reservoir and the pumping chamber, theback-flow through the outlet valve being small, and thus the effectivestroke volume is expected to be very close to the nominal stroke volume.

In case of a higher probability to get particles or permanent opening onthe outlet valve, pumping cycles made preferably or only of cycles Bshould be preferred.

To summarize, if by design or process considerations the probability tohave a residual fluidic resistance of the outlet (resp. inlet) valvelarger than the residual fluidic resistance of the inlet (resp. outlet)valve is high (close to 1), the pumping pattern should comprisepreferably (or only) cycles of A (resp. B) type. In another word, ifthere is a leakage at the inlet (resp. outlet), the pumping patternshould comprise preferably (or only) cycles of A (resp. B) type.

This method is an approximation of the complete method based on the useof alternated cycles as described previously. This alternative method ishowever simpler in term of software development since the detectionalgorithms should be implemented for either cycles A or cycles B whilefor the complete method the detection algorithms for both kinds ofcycles A and B shall be implemented.

Moreover, since this method is based on the use of a single kind ofactuation cycles A or B, it is no longer necessary to compensate piezohysteresis effect as varies the actuation frequency, leading again tosimpler delivery algorithms.

1.5. Detailed Method for Bolus Infusion

Pumping Chamber Elasticity and Bolus Stroke Volume

We analyse the volume change at the inlet, the pumping chamber and theoutlet during each step of the bolus pumping profile, making a completecycle from an initial position against one mechanical stop, andconsidering two extreme cases:

-   -   No pressure relaxation except during the release of the membrane        at the end of the bolus (=pump very tight)    -   Full relaxation of the pressure after each move of the membrane        (=pump safe but at the limit of the specifications in term of        tightness)

The volume infused during each step of the bolus stroke is estimated.

The tables 7 and 8 summarize the results.

TABLE 7 Volume changes during bolus strokes for very tight pumps. Pumpstatus Pchamber V inlet Vchamber V outlet Full pull (ret) −P_(val) 0V₀ + S_(v) − dV 0 Full push +P_(val) 0 V₀ + dV S_(v) − 2dV Full pull−P_(val) S_(v) − 2dV V₀ + S_(v) − dV S_(v) − 2dV

TABLE 8 Volume changes during bolus strokes for pumps at the limit ofthe specifications in term of leakage. Pump status Pchamber V inletVchamber V outlet Full pull (ret) −P_(val) 0 V₀ + S_(v) − dV 0 Full pull(relax) 0 −dV₁ V₀ + S_(v) −dV₂ Full push +P_(val) −dV₁ V₀ + dV S_(v) −dV − dV₂ Full push (relax) 0 0 V₀ S_(v) − dV Full pull −P_(val) S_(v) −dV V₀ + S_(v) − dV S_(v) − dV

We obtain:

${S_{v}({bolus})} = {S_{v} - {\frac{3\;{dV}}{2} \pm \frac{dV}{2}}}$

Finally, considering the tolerance of 20% on the valve pretension, weobtain a typical infusion error due to elasticity equal to:error(bolus stroke)=±0.384 nl

During the last half stroke at the end of the bolus infusion whichcorresponds for instance to the release of the membrane from the bottomto the rest position, there is a max punctual error of few nl due to theelasticity of the “free” membrane as discussed for basal infusion.

Bolus Delivery Algorithm

In bolus mode, the patient programs a volume of insulin V_(bolus) to beinfused within a short period. The volume V_(bolus) varies typicallyfrom 0 to 25 U with typical steps of 0.02 U.

According to the method described above for basal delivery, it could beuseful to adjust by design the nominal basal stroke volume to a multipleof the minimum increment of the infused volume that can be programmedevery hour and/or the minimum increment for a bolus volume.

In this latter case, the bolus stroke volume will not be a perfectmultiple of said minimum programmable increment (for instance 0.02 U),and a bolus delivery algorithm should be implemented to calculate thenumber of bolus stroke to be delivered.

The Pump Controller divides V_(bolus) by the nominal bolus strokevolume:

$n = \frac{V_{bolus}}{S_{v}({bolus})}$

The number of stroke N to be delivered is simply the integer nearest ofn.

We note └n┘ the floor (or integer part) of n, respectively the largestinteger not greater than n.

If n−└n┘>0.5, then N=└n┘+1

If n−└n┘≤0.5, then N=└n┘

The max absolute error is equal to

$\frac{S_{v}({bolus})}{2}$for any programmed V_(bolus). There is no accumulated error.

According to FIG. 4, the relative error as a function of the programmedbolus volume illustrates this feature.

To compensate the mismatch between the bolus stroke volume and theincrement of bolus volume, a bolus algorithm is implemented and leads toa max relative error lower than +/−0.2% for bolus of 5 U or more.

The minimum bolus is equal to S_(V)(bolus) and therefore the max errorfor any bolus volume is equal to +/−S_(V)(bolus)/2.

This bolus algorithm is a non-limiting example of the present invention.

Any other method using another rounding calculation, for any othernominal stroke volume can be used as bolus algorithm.

According to the methods described in the present invention, the pumpingdevice should include means to compute the pumping pattern using nominalstroke volumes different for basal and bolus infusion.

The invention claimed is:
 1. A method for actuating a pumping system toimprove fluid delivery accuracy, the pumping system including, a pumpingchamber having an inlet channel and an outlet channel, a pumpingmembrane in operative connection with the pumping chamber, an actuatoroperatively coupled to the pumping membrane, the pumping membraneconfigured to be pushed by the actuator to generate a positive pressureof a fluid in the pumping chamber and configured to be pulled by theactuator to generate a negative pressure of the fluid in the pumpingchamber, and a pump controller configured to control the actuatoraccording to a pumping pattern including a first pumping cycle and asecond pumping cycle, the first pumping cycle beginning by a partialpush and ending by a partial push of the membrane by the actuator, andthe second pumping cycle beginning by a partial pull and ending by apartial pull of the membrane by the actuator, wherein the methodincludes the steps of: performing the pumping pattern with a firstdetermined number of the first pumping cycle followed by a seconddetermined number of the second pumping cycle or vice versa, wherein thefirst determined number and the second determined number are integernumbers that are not zero.
 2. The method for actuating the pumpingsystem according to claim 1, further comprising the step of: performinga stationary phase in which the membrane is not moved by the actuator,the stationary phase permitting a relaxation of a pressure in thepumping chamber to an equilibrium pressure.
 3. The method for actuatingthe pumping system according to claim 2, wherein the pumping systemincludes an inlet valve at the inlet channel and an outlet valve at theoutlet channel, and wherein during the stationary phase, a change of avolume of the fluid present in the pumping chamber is induced by a flowof the fluid through both the inlet valve and the outlet valve.
 4. Themethod for actuating the pumping system according to claim 1, whereinthe partial pull performs a partial suction phase of the fluid in thepumping chamber, and the partial push performs a partial discharge phaseof the fluid in the pumping chamber.
 5. The method for actuating thepumping system according to claim 1, wherein a hysteresis effect iscaused by the actuator and the pumping membrane, the hysteresis effectincluding a difference between an original rest positions and a restposition of the pumping membrane after the step of performing thepumping pattern.
 6. The method for actuating the pumping systemaccording to claim 5, further comprising a step of: repeating the stepof performing the pumping pattern to reduce the effect of thehysteresis.
 7. The method for actuating the pumping system according toclaim 1, further comprising the step of: alternating of a number of thefirst pumping cycle followed and a number of the second pumping cycle.8. The method for actuating the pumping system according to claim 1,wherein the first determined number is equal to the second determinednumber.
 9. The method for actuating the pumping system according toclaim 1, further comprising a step of: computing an error estimation dueto an hysteresis effect.
 10. The method for actuating the pumping systemaccording to claim 1, further comprising a step of: computing acompensation volume due to an hysteresis effect.
 11. The method foractuating the pumping system according to claim 1, further comprising astep of: performing a compensation step to compensate an infusion errordue to an hysteresis effect.
 12. The method for actuating the pumpingsystem according to claim 1, further comprising a step of: increasing atleast one of the first determined number and the second determinednumber in order to reduce the relative error due to the hysteresis orrelaxation.
 13. The method for actuating the pumping system according toclaim 1, wherein at least one partial pull is performed in order toreach a rest position of the pumping membrane.
 14. The method foractuating the pumping system according to claim 1, wherein at least onepartial push is performed in order to reach a rest position of thepumping membrane.
 15. The method for actuating the pumping systemaccording to claim 1, wherein at least one partial push is performedwithout powering the actuator.
 16. The method for actuating the pumpingsystem according to claim 1, wherein the first pumping cycle furthercomprises a full pull.
 17. The method for actuating the pumping systemaccording to claim 1, wherein the second pumping cycle further comprisesa full push.
 18. A method for actuating a pumping system to improvefluid delivery accuracy, the pumping system including, a pumping chamberhaving an inlet channel and an outlet channel, a pumping membrane inoperative connection with the pumping chamber, an actuator operativelycoupled to the pumping membrane, the pumping membrane configured to bepushed by the actuator to generate a positive pressure of a fluid in thepumping chamber and configured to be pulled by the actuator to generatea negative pressure of the fluid in the pumping chamber, and a pumpcontroller configured to control the actuator according to a pumpingpattern including a first pumping cycle and a second pumping cycle, thefirst pumping cycle beginning by a partial push and ending by a partialpush of the membrane by the actuator, and the second pumping cyclebeginning by a partial pull and ending by a partial pull of the membraneby the actuator, wherein the method includes the steps of: performingthe pumping pattern with a first determined number of the first pumpingcycle followed by a second determined number of the second pumping cycleor vice versa, wherein the first determined number and the seconddetermined number are integer numbers that are not zero, and wherein thefirst determined number is equal to the second determined number.